Rapidly resorbable glibenclamide

ABSTRACT

A blood sugar lowering composition comprising as the active material particulate glibenclamide having a surface area of about 3 to 10 m 2  /g in admixture with a pharmacologically acceptable non-ionic wetting agent present in about 2 to 20 times the weight of the glibenclamide. The preferred wetting agent is polyoxyethylene stearate present in about 5 to 10 times the weight of the glibenclamide.

The instant application is a continuation-in-part of application Ser.No. 508,001, filed Sept. 20, 1974, now U.S. Pat. No. 3,979,520.

THE PRESENT INVENTION IS CONCERNED WITH A NEW FORM OFN-4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl-sulfonyl-N'-cyclohexylurea.

N-4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl-sulfonyl-N'-cyclohexylureais a highly effective chemotherapeutic agent which is also known as"glibenclamide" and as "HB 419". It is a recent sulfonylurea derivativewith the greatest hitherto known blood sugar lowering action and thelowest degree of side effects so that it is especially suitable for thetreatment of diabetes mellitus.

It is known that the therapeutic value of an active material can depend,to a large extent, upon the form of administration and the formulationemployed. This also applies to glibenclamide (see W. Rupp, O. Christ andW. Fulberth, Arzneimittel-Forschung (Drug. Res.), 22, 471-473/1972). Inparticular, a prerequisite for dependable action is resorption of theactive material from a pharmaceutical preparation as completely aspossible. This prerequisite is fulfilled for the glibenclamide incommercially available preparations. In pharmacokinetic studies, it hasbeen demonstrated that a practically complete intestinal resorptiontakes place from the commercially available forms (see W. Rupp et al.,loc. cit.).

It is generally known that the degree of resorption of sparingly solubleactive materials depends upon their degree of division, i.e. particlesize. In the commercial preparation, glibenclamide is present in theform of particles with a surface area of 1-2 m² /g. This fine degree ofdivision is the prerequisite for the 100 percent degree of resorptionachieved with this preparation.

We have now, surprisingly, found that with the preparations according tothe present invention, by increasing the particle surface area to atleast 3 m² /g the complete resorption is retained along with a markedlymore rapid lowering of the blood sugar than with the previously knownpreparations.

The more rapid resorption has two main advantages:

A. SINCE THE TABLETS ARE ADMINISTERED SIMULTANEOUSLY WITH A MEAL, THEACTIVE MATERIAL PASSES, TOGETHER WITH THE CARBOHYDRATES, INTO THEORGANISM SO THAT THE NEED FOR THE ACTIVE MATERIAL AND ITS SUPPLY ARESYNCHRONIZED; AND

B. IN THE CASE OF SLOWER RESORPTION, THERE IS THE DANGER THAT, SEVERALHOURS AFTER ADMINISTRATION, SIGNIFICANT AMOUNTS OF ACTIVE MATERIALCONTINUE TO BE RESORBED WITHOUT A CORRESPONDING SUPPLY OF CARBOHYDRATES.In this way, hypoglycaemias can occur. This danger is overcome by themore rapid resorption.

It is economically advantageous that the forms of administrationaccording to the present invention can be produced in a technicallysimple manner by means of working methods which are conventional in thepharmaceutical industry. Thus, we have found that the active materialmust be present in an especially fine state of division with a particlesurface area of at least 3 m² /g in order to achieve the above-mentionedincrease of the blood sugar-lowering action. The fine crystallizateaccording to the present invention can be worked up to conventionalpharmaceutical compositions, for example, tablets, dragees or capsules,by admixture with solid or liquid pharmaceutical diluents or carriers.Each such unit dose contains about 0.5 to 10 mg and preferably about 1to 5 mg of active material.

For the production of tablets and dragees, which represent the preferredforms of administration for this oral antidiabetic, there can be usedall the conventional tablet adjuvants. Although the mechanism of themanner of working of dispersion agents added according to the presentinvention has still not been fully elucidated, it is to be assumed thatdispersion agents prevent an aggregation of the very fine particles ofthe active material in the alimentary tract and thus assist theresorption thereof. Therefore, according to the present invention, theterm "dispersion agent" is to be broadly interpreted and is to beunderstood to include all materials which prevent a reagglomeration ofthe finely-divided glibenclamide. In the case of administration of theglibenclamide in tablet form, there can already be present substancessuch as polyglycols, lactose, starch, cellulose and the like, which alsofunction as dispersion agents when they are present in large excess.

However, it has proved to be especially advantageous, as additionaldispersion agent, also to incorporate a wetting agent into the tabletmass. Per one part of the glibenclamide, it is sufficient to use about 2to 100 l and preferably about 2 to 20 parts of the wetting agent inorder to bring about the resorption requirements according to thepresent invention, a ratio of about 1:5 to 1:10 being especiallypreferred. As wetting agent, it has proved to be especially useful toemploy polyoxyethylene stearate but other wetting agents can also beused insofar as they are pharmacologically compatible.

The process according to the present invention for the production of ahighly effective, completely resorbed form of administration ofglibenclamide is characterized in that the glibenclamide is brought to aparticle surface area of at least 3 m² /g by precipitation from asolution or by grinding, followed by mixing with a dispersion agent.

Degrees of division of this order can only be achieved by grinding withvery great difficulty. We have found that grinding 3 or 4 times with ajet mill, possibly with the addition of milling adjuvants, just sufficesto achieve a particle surface area of 3 m² /g, corresponding to aparticle size of about 2μ.

The fine crystallizate according to the present invention with a surfacearea of at least 3 m² /g, and preferably of about 5-10 m² /g, ispreferably achieved by precipitation of the glibenclamide from asolvent.

It has proved to be especially useful to dissolve the glibenclamide in awater-miscible organic solvent and to introduce this solution,preferably with intensive mixing, into a weakly acidified aqueousmedium. The choice of the solvent is, in itself, not critical; allsolvents can be used which dissolve the glibenclamide in sufficientamounts. Preferably there are used lower alcohols, e.g. lower alkanolsof up to about 4 carbon atoms, dimethyl formamide or dimethyl sulfoxide.

Since the solubility of glibenclamide in water reaches a minimum at a pHof 4, the aqueous medium is preferably acidified somewhat. As acid, ithas proved to be especially useful to employ acetic acid, citric acid,ascorbic acid, or the like.

According to a further variant of the process, either a soluble salt ofglibenclamide is directly dissolved in water or in an aqueous alcohol orthe glibenclamide is introduced into a calculated amount of an aqueoussolution of an alkali metal hydroxide and the solution thus obtained isthen introduced into a weakly acidified aqueous medium. A disadvantageof this process has been found to be that, in the case of comparativelylarge batches, considerable amounts of heat of neutralization must beremoved but, on the other hand, the substantially simpler handling ofaqueous solutions in comparation with the use of organic solvents isadvantageous. In the case of this process, too, ascorbic acid, aceticacid or citric acid is preferably used for the neutralization since withthese acids the optimum pH range of about 4 to 7 for the precipitationcan be controlled especially easily.

In the synthesis of glibenclamide, there is obtained a pure crystallineproduct with a particle size of about 50-1000μ and a melting point of172°-174° C. For further working up into pharmaceutical compositions,this product is usually ground to a particle size of about 10μ, i.e. aparticle surface area of about 1 m² /g and worked up, with the necessaryadditives, into tablets or dragees. The forms of administrationaccording to the present invention contain the glibenclamide with aparticle surface area of at least 3 m² /g, i.e. a particle size of atmost 2μ. In this previously unknown degree of division, glibenclamideshows, surprisingly, even a melting point depression or an increase ofthe melting range. Furthermore, since the substance is absolutely pure,this is to be attributed to the increased surface energy of the smallparticles.

The preparation of glibenclamide with a surface area, according to theinvention, of 3-10 m² /g is illustrated by the following Examples, thesurface areas given therein being determined by the BET method (seeBrunauer, Emmet and Teller, J.A.C.S., 60, 309-319/1938).

EXAMPLE 1

50 g of glibenclamide are dissolved at 40°-50° C in 116 g of dimethylformamide. This solution is then run, with intensive stirring, intoabout 1 liter of cold water. The glibenclamide is thus obtained as afinely-divided suspension which is filtered off and copiously washedwith water. After drying at 50° C., the yield is 90-95%. The product hasa particle surface area of 5.79 m² /g. The melting point is 170.5°-172°C.

EXAMPLE 2

50 g of glibenclamide are dissolved in 100 ml of dimethyl formamide,with gentle warming at 47° C. In a 3 liter tubular vessel there isplaced a solution of 20 g of citric acid in 980 ml of water. An UltraTurrax turbine stirrer (type T 45 N) dips into the solution. Whilestirring at 5000 rpm, the dimethylformamide solution of glibenclamide isuniformly added, via a dropping funnel, a tube and a thin canula,directly into the suction opening of the stirrer head over the course of5 minutes. The temperature increases from 20° to 41° C. The suspensionobtained thereafter is immediately filtered off with suction. Thesubstance is washed with water and dried at 60° C in a circulating aircabinet. The yield is 48.5 g (97% of theory) and the product has amelting point of 166°-169° C and a particle surface area of 9.8 m² /g.

EXAMPLE 3

50 g of glibenclamide are dissolved in 100 ml of dimethyl formamide, 6 gof glacial acetic acid are dissolved in 1 liter of water in a 3 litertubular vessel. The experimental procedure is as described in Example 1.In addition, a cooling coil dips into the solution. While stirring at5000 rpm and cooling with ice water, the dimethyl formamide solution ofglibenclamide is introduced into the suction opening of the stirrer headover the course of 2 minutes. The temperature increases from 6° to 13°C. Subsequently, the product is filtered off with suction, washed withwater and dried at 60° C. The yield is 46.8 g (97.6% of theory) and theproduct has a melting point of 170°-172° C and a particle surface areaof 6.0 m² /g.

EXAMPLE 4

400 g of glibenclamide are dissolved in 8000 ml of dimethyl formamide atabout 50° C (Solution 1). 2750 ml of 2N acetic acid are diluted with 50liters of water (Solution 2). A solution of 55 ml of 2N acetic acid in 1liter of water is placed in a 3 liter tubular vessel equipped with acooling coil and an Ultra Turrax stirrer. While stirring at 5000 rpm, bymeans of a dosing pump, Solutions 1 and 2 are pumped into the stirrerhead at the respective rates of addition of 1 liter per hour and 65liters per hour. The temperature is 8° C. The volume in the vessel iskept constant by constantly withdrawing the suspension formed from aboveinto a suction flask. Alternatively, an overflow can be used. Thesuspension is filtered with suction and the product obtained is washedwith water and dried at 60° C. The yield is 97% of theory. The producthas a melting point of 169.5°-172° C and a particle surface area of 6.8m² /g.

EXAMPLE 5

100 g of the sodium salt of glibenclamide are dissolved at 35° C in amixture of 1340 ml of methanol and 176 ml of water, treated with 2.8 gof active charcoal, filtered and the charcoal washed with a mixture of40 ml of methanol and 6 ml of water. In a 3 liter tubular vessel thereis placed a solution of 12 g of glacial acetic acid in 1 liter of water.While stirring at 500 rpm and cooling with ice water, the methanolicsolution is allowed to run in via a dropping funnel and canula into thesuction opening of the stirrer head of the stirrer used over the courseof 7 minutes. The temperature increases from 9° to 19° C. The suspensionis filtered off with suction, washed with water and dried at 60° C. Theyield is 94% of theory and the product has a melting point of 164°-168°C and a particle surface area of 10.3 m² /g.

EXAMPLE 6

2.7 kg of glibenclamide are dissolved at about 50° C in 5.4 liters ofdimethyl formamide. A solution of 350 ml of glacial acetic acid in 54liters of water is placed in a 100 liter V4A steel vessel. The solutionis cooled by standing the 100 liter V4A steel vessel in a larger vesselfilled with ice water. An Ultra Turrax turbine stirrer (type T 115) dipsinto the acetic acid solution. While stirring at 2300 rpm, the dimethylformamide solution of glibenclamide is fed by means of a dosing pump atthe rate of 13 liters per hour directly into the suction opening of thestirrer head. The temperature increases from 11° to 17° C. Thesuspension is filtered off with suction or is forced through a filter.The product is washed with water and dried at 60° C. The yield is 97% oftheory and the product has a melting point of 172°-173° C and a particlesurface area of 5.2 m² /g.

EXAMPLE 7

3 kg of the sodium salt of glibenclamide are dissolved at 35° C in amixture of 40 liters of methanol and 5.3 liters of water, treated with85 g of charcoal and filtered. A solution of 380 ml of glacial aceticacid in 30 liters of water are placed in a 100 liter V4A steel vesselcooled with ice water. While stirring at 2300 rpm and cooling with icewater, the filtered methanolic solution of the sodium salt ofglibenclamide is dosed directly into the stirrer head at a rate of about60 liters per hour. The temperature increases from 7° to 22° C. Thesuspension is filtered off with suction or is forced through a filter,washed with water and dried at 60° C. The yield is 94% of theory and theproduct has a melting point of 166°-168° C and a particle surface areaof 7.8 m² /g.

EXAMPLE 8

2 kg glibenclamide with a particle size of 5-300 μ are passed threetimes through a jet mill. The yield is 1.8 kg (90% of theory) and theproduct has a melting point of 170°-172° C and a particle surface areaof 5.8 m² /g.

The administration of oral anti-diabetic substances to fasting healthysubjects leads, as a rule, to a shorter time interval during which theblood sugar level is lowered, since the lower blood glucoseconcentrations prematurely initiate counter-regulatory processes.Therefore, in testing for activity an attempt is made to achieve, bymeans of continuous glucose infusion, a blood sugar level which is asconstant as possible, of the order of 120 mg/100 ml by continuousinfusion of glucose to test subjects. With the continuous administrationof glucose, the anti-diabetic substance should only reduce the bloodsugar concentration to such an extent that the counter-regulation bringsabout the smallest possible shortening of the blood sugar loweringbrought about by the test substance. By the administration of 14 g ofglucose per hour to fasting healthy subjects with a body weight of 70kg, in 20 blank experiments it was possible to achieve, with a glucoseinfusion for 7.25 hours, a satisfactorily constant blood sugar level ofthe order of 120 mg/100 ml. The blood sugar controls were carried outafter the commencement of the infusion at 15 minute intervals; in all,using the hexokinase method (micromethod), 31 blood sugar determinations(including two blanks before commencement of the infusion) were made persubject.

In the case of the test substance experiments, under otherwise the sameexperimental conditions, the test preparation in question wasadministered 1.75 hours after commencement of the glucose infusion. Theexperiments were ended, in each case, 7.25 hours after commencement ofinfusion or 5.5 hours after administration of the test substance, alonger period of infusion not being practical.

The following preparations were administered:

1. A suspension of 1.25 mg of glibenclamide, initially dissolved in 10ml of water in the form of its sodium salt and precipitated with about1.0 mg of crystalline ascorbic acid.

2. One half of a tablet according to the present invention of oblongshape and consisting of:

    ______________________________________                                        1.25      mg    glibenclamide                                                                             (particle surface area                                                        5.35 m.sup.2 /g)                                  10.00     mg    polyoxyethylene stearate                                      23.75     mg    lactose                                                       5.00      mg    corn starch                                                   25.00     mg    sodium bicarbonate                                            3.50      mg    highly-dispersed silicic acid                                 16.00     mg    urea                                                          0.50      mg    magnesium stearate                                            85.00     mg                                                                  ______________________________________                                    

3. Half of a commercially available tablet consisting of:

    ______________________________________                                        2.5       mg    glibenclamide                                                                             (particle surface area                                                        about 1 m.sup.2 /g)                               39.5      mg    lactose                                                       35.25     mg    corn starch                                                   1.50      mg    talc                                                          0.25      mg    magnesium stearate                                            1.00      mg    highly dispersed silicic acid                                 80.00     mg                                                                  ______________________________________                                    

The blood sugar values measured over the course of time is shown in FIG.1 of the accompanying drawings, curves 1, 2 and 3 corresponding to theabove-described preparations 1, 2, and 3.

The parameters determined, which are representative for the experiments,are set out in the following Table:

                                      TABLE 1                                     __________________________________________________________________________                                        HB 419 - Commercial                       Representative Parameter                                                                              HB 419 - Suspension                                                                       Oblong Tablet                                                                          preparation                      __________________________________________________________________________    Number of test subjects 21          19       17                               dosage         (mg)     1.25        1.25     2.5                              blood sugar level                                                             (before action)                                                                              (mg/100 ml)                                                                            122.1       123.7    116.8                            commencement of action                                                                       (h)      2.23        2.10     2.42                             absorption delay                                                                             (h)      0.49        0.36     0.67                             minimum blood sugar                                                                          (mg/100 ml)                                                                            53.4        57.4     59.1                             time of minimum blood sugar                                                   (before commencement of                                                       action)        (h)      1.10        1.45     2.43                             blood sugar level                                                             (end of action)                                                                              (mg/100 ml)                                                                            99.2        101.6    97.6                             period of action                                                                             (h)      3.01        3.95     4.76                             area of action (mg/100 ml . h)                                                                        125.1       159.8    155.5                            rate of increase of the                                                       action         (mg/100 ml/h)                                                                          62.6        45.9     23.7                             __________________________________________________________________________

The following additional tests were carried out: Test compositions wereadministered by a stomach tube to fasting rabbits of both sexes, with anaverage weight of about 2 kg., as a suspension in water. To prepare thesuspension the tablets were crushed in a sufficient amount of water andsuspended by vigorous stirring. 0.1 ml/kg body weight of thesesuspensions were given in a suitable concentration.

For the testing of the blood-sugar-depressing effect of the compositionsthe compositions were administered after a fasting period of 16 hours.Just prior to administration of the test compositions and during theentire course of the test, blood samples were taken and blood sugardeterminations were conducted. The blood samples of 0.01 ml wereobtained from an ear vein and blood sugar was determined by way of theaccepted HK-technique (F. H. Schmidt et al., "Enzymatic determination oftriglycerides in blood and blood glucose by automated methods",Automatisation et Biologie Prospective, Pont-a-Mousson, 9. -14/10/1972). The HK-technique is accepted world-wide as a referencemethod since it is regarded as absolutely foolproof.

In each test series, a control group was tested side-by-side with theanimals which had been injected with the test compounds; the animals inthe control group were administered sodium chloride instead of the testsubstance and blood sugar determinations were made in the same manner asdescribed above. Accordingly, any statistically significant deviationsbetween the control group animals and those treated with the testcompounds in blood sugar depressing properties were considered as causedby the test substance. Using a test animal group consisting of fiveanimals, deviations of at least 10 to 15% were regarded as statisticallysignificant.

                  TABLE 2                                                         ______________________________________                                                                  Threshold                                           Composition               Dosage                                              ______________________________________                                        1)  Suspension of commercial glibenclamide                                        tablets according to preparation 3                                                                      50 μg/kg                                     2)  Suspension of commercial glibenclamide                                        tablets according to preparation 3,                                           with added dispersing agent                                                   (10.0 mg polyoxyethylene stearate)                                                                      50 μg/kg                                     3)  Suspension of microfine glibenclamide                                         tablets according to preparation 2,                                           but                                                                           without the polyoxyethylene stearate                                                                    100 μg/kg                                    4)  Suspension of microfine glibenclamide                                         tablets according to preparation 2,                                                                     25 μg/kg                                     ______________________________________                                    

The above data show that neither the dispensing agent nor the microfinedistribution of the glibenclamide has a positive effect on theresporption of glibenclamide from the intestine and that surprisinglythe combination of both elements remarkably improves the resorption andthereby diminishes the effective dosage.

The same test procedure was used with different formulations employing avariety of surface areas and ratios of wetting agents to glibenclamide.In addition, a variety of wetting agents were employed, showing thesuperiority of the non-ionic wetting agents of which polyoxyethylenestearate is representative. The results were as follows:

                  TABLE 3                                                         ______________________________________                                                                 Threshold                                            Compositon               Dosage                                               ______________________________________                                        5)  Suspension of microfine gliben-                                               clamide tablets according to                                                  formulation 2, with                                                           a particle surface area of the                                                glibenclamide of 3.4, 5.5, 8.5                                                and 9.8 m.sup.2 /g and a polyoxyethylene                                      stearate content of the 5 fold and                                            10 fold amount of the glibenclamide                                                                    20 - 25 μg/kg                                 6)  Suspension of microfine gliben-                                               clamide tablets according to                                                  a particle surface area of 7.0 m.sup.2 /g                                     and an 8 fold weight of polyoxy-                                              ethylene sorbitan fatty acid ester                                            (trademark Tween 65)     37 μg/kg                                      7)  Suspension of microfine gliben-                                               clamide tablets according to                                                  formulation 2, with                                                           a particle surface area of 5.5,                                               7.0, 9.8 m.sup.2 /g and a 2 fold to                                           20 fold amount of polyoxyethylene                                             monostearate (trademark Myrj 52)                                                                       20 - 25 μg/kg                                 8)  Suspension of microfine gliben-                                               clamide tablets according to                                                  formulation 2, with                                                           a particle surface area of 7.0 m.sup.2 /g                                     and an 8 fold amount of polyoxyethylene                                       ethyl ether (trademark Brij 58)                                                                        25 μg/kg                                      9)  Suspension of microfine gliben-                                               clamide tablets according to                                                  formulation 2, with a                                                         particle surface area of 7.0 m.sup.2 /g and                                   a 5 fold and 10 fold amount of sodium-                                        laurylsulfate (trademark Texapon)                                                                      100 μg/kg                                     ______________________________________                                    

It will be appreciated that the instant specification and examples areset forth by way of illustration and not limitation, and that variousmodifications and changes may be made without departing from the spiritand scope of the present invention.

What we claim is:
 1. A blood sugar lowering composition comprisingmicrofine particulate glibenclamide having a surface area of about 3 to10 m² /g in admixture with a pharmacologically acceptable non-ionicwetting agent present in about 2 to 20 times the weight of theglibenclamide.
 2. The composition of claim 1, wherein the activematerial has a particle surface area of 5 to 10 m² /g.
 3. Thecomposition of claim 1, wherein the dispersion agent is present in about5 to 10 times the weight of the glibenclamide.
 4. The composition ofclaim 1, wherein the wetting agent is polyoxyethylene stearate.
 5. Aunit dose of the composition of claim 4, wherein the glibenclamide ispresent in about 0.5 to 10 mg and the polyoxyethylene stearate ispresent in about 5 to 10 times the weight of the glibenclamide.